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Study of novel biosynthetic pathway of BH_4 which concern human aldo-keto reductases

人醛酮还原酶BH_4新生物合成途径的研究

基本信息

批准号：
16591059
负责人：
IINO Teruhiko
金额：
$ 2.3万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Tetrahydrobiopterin (BH_4) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthesis includes two reduction steps catalyzed by sepiapterin reductase.PPH_4 is reduced to 6-(1'-oxo-2'-hydroxypropyl)-tetrahydropterin (1'-OXPH_4) or 6-(1'-hydroxy-2'-oxopropyl)-tetrahydropterin (2'-OXPH_4), which is further converted to BH_4.In 2001, sepiapterin reductase (SPR) deficiency was reported in dystonia like disease. However. patients with SPR deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting the existence of another BH_4 biosynthetic pathway, which is not concerned with SPR in humans.Recently. we reported a new SPR-unrelated BH_4 formation route from PPH_4, in which human aldo-keto reductase (AKR1C3 and AKR1B1) work in concert.. In the reduction of PPH_4 by AIM family enzymes, 2'-OXPH_4 was formed by 3α-hydroxysteroid dehydrogenase type 2(AKR1C3), whereas 1'-OXPH_4 was produced by aldose reductaseUK.R1B1), respectably.Blau et al. proposed a BH_4 biosynthetic salvage pathway containing nonenzymatic conversion of 1'-OXPH_4 to sepiapterin. In this study, the possibility of the nonenzymatic conversion of 1'-OXPH_4 to sepiapterin was examined by using human aldo-keto reductase(AKR1B1) and human monomeric carbonyl reductase. Since 1'-OXPH_4 has been suggested to be nonenzymatically converted into sepiapterin, in an incubation mixture containing PPH_4 and AKR1B1, sepiapterin was determined by its derivative as biopterin. No sepiapterin was detected in the incubation mixture when the mixture containing 800 pmol of 1'-OXPH_4 was further incubated at 37℃ for 2 h in darkness. This result suggests that the rate of the nonenzymatic formation of sepiapterin from 1'-OXPH_4 is quite low. The findings obtained here indicate that the proposed pathway in which a nonenzymatic conversion of 1'-OXPH_4 to sepiapterin occurs may be difficult or unlikely to proceed in humans.

四氢生物蝶呤（BH_4）是芳香氨基酸羟化酶和一氧化氮合酶的辅助因子。该生物合成包括两个还原步骤，由七叶皂苷还原酶催化。PPH_4还原为6-（1'-氧-2'-羟丙基）-四氢蝶呤（1'- oxph_4）或6-（1'-羟基-2'-氧丙基）-四氢蝶呤（2'- oxph_4），进一步转化为BH_4。2001年，在肌张力障碍样疾病中报道了sepapterin还原酶（SPR）缺乏症。然而。SPR缺乏症患者尿中蝶呤排泄正常，无高苯丙氨酸血症，提示存在另一种与人类SPR无关的BH_4生物合成途径。我们报道了一个与spr无关的PPH_4形成BH_4的新途径，其中人类醛酮还原酶（AKR1C3和AKR1B1）协同工作。AIM家族酶还原PPH_4时，2′-OXPH_4由3α-羟基类固醇脱氢酶2型（AKR1C3）生成，1′-OXPH_4由醛糖还原酶euk生成。R1B1),体面地。Blau等人提出了一种BH_4生物合成回收途径，该途径包含1'-OXPH_4到sepapterin的非酶转化。本研究利用人醛酮还原酶（AKR1B1）和人单体羰基还原酶，考察了1′-OXPH_4非酶转化为七叶黄素的可能性。由于1'-OXPH_4被认为可以非酶转化为sepapterin，在含有PPH_4和AKR1B1的孵育混合物中，sepapterin被确定为生物蝶呤（biopterin）。将含有800 pmol 1′-OXPH_4的培养液在37℃、黑暗条件下孵育2 h后，未检测到sepapterin。这一结果表明，1′-OXPH_4非酶促生成七叶蝶呤的速率很低。本文的研究结果表明，1'-OXPH_4非酶转化为sepapterin的途径可能很难或不太可能在人类中进行。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Possibility of the Nonenzymatic Conversion of 6-(1'Oxo-2'-hydroxypropyl)-Ttrahydrobiopterin to Sepiapterin

6-(1Oxo-2-羟丙基)-四氢生物蝶呤非酶转化为墨蝶呤的可能性

DOI：
发表时间：
2005
期刊：
Pteridines 16
影响因子：
0
作者：
Mahler M;Kessenbrock K;Szmyrka M;Takasaki Y;et al.;H.Sawada et al.
通讯作者：
H.Sawada et al.

Analysis of genes related to expression of aromatase and estradiol-regulated genes during sex differentiation in Xenopus embryos.

DOI：
10.1016/j.ygcen.2004.01.014
发表时间：
2004-05
期刊：
General and comparative endocrinology
影响因子：
2.7
作者：
N. Akatsuka;Hiroshi Kobayashi;E. Watanabe;T. Iino;K. Miyashita;S. Miyata
通讯作者：
N. Akatsuka;Hiroshi Kobayashi;E. Watanabe;T. Iino;K. Miyashita;S. Miyata

Molecular poprerties and tissue distribution of 30K proteins as ommim-binding proteins from diapause eggs of the silkworm. Bombyx mori

家蚕滞育卵中 30K 蛋白作为 ommim 结合蛋白的分子特征和组织分布。

DOI：
发表时间：
2007
期刊：
Comparative Biochemistry and Physiology B (In Press)
影响因子：
0
作者：
Thorburn DR;Sugiana C;Salemi R;Kirby DM;Worgan L;Ohtake A et al.;Kawashima H et al.;大竹明;T.Makayama et al.;H.Sawada
通讯作者：
H.Sawada

A novel RNA helicase-like protein during early embryonic development in silkworm Bombyx mori:: Molecular characterization and intracellular localization